Both methamphetamine and MPTP are toxic to dopamine neurons in the adult human and adult, non-human primate through mechanisms involving oxidative stress. Recent findings, supported by a R21 NINDS grant, have demonstrated a remarkable resistance to both methamphetamine and MPTP in the infant and late- gestational fetal monkey and raised questions concerning differences in the mechanisms of oxidative stress in developing dopamine neurons. Other studies supported by this exploratory grant have identified a time period that primate dopamine neurons undergo apoptotic natural cell death. During the peak of natural cell death, fetal dopamine neurons were sensitive to the toxic effects of methamphetamine or MPTP. Together these studies identify a vulnerable window in gestation where methamphetamine or MPTP are toxic to the immature dopamine neurons, potentially through developmental changes in the response to oxidative stressors. The proposed studies will pursue these findings by investigating the mechanism(s) of the differential sensitivity to the effects of MPTP and methamphetamine during development and in adult monkeys. We will examine the biochemical response of the midbrain dopamine system to MPTP and methamphetamine at various stages of development, to see whether differences in degree of oxidative stress, uncoupling protein-2 activity, neurotrophic factors, and glutamate innervation of the substantia nigra and/or DNA repair mechanisms explain the observations. This work has relevance to the etiology and treatment of neurological and psychiatric disorders that may be initiated by damage to developing dopamine neurons. Besides being models of oxidative stress, the actual drugs used in the studies also have clinical relevance. MPTP is structurally related to herbicides that have been implicated in Parkinson's disease. Methamphetamine is currently a widely abused drug, yet there have been no previous studies on the toxicity of methamphetamine on developing primate brain dopamine neurons. This research will enhance our biochemical understanding of the changing vulnerability of the developing brain dopamine neurons to oxidative stress, and may identify strategies for protecting dopamine neurons from neurodegeneration. PUBLIC HEALTH RELEVANCE: Our data shows that exposure to oxidative stress at a certain period in primate development induces exaggerated damage to dopamine neurons in the brain. The drugs methamphetamine or MPTP are administered to produce an oxidative stress model in the monkey. The studies have direct relevance to the risk of acquiring Parkinson's disease and to the behavioral consequences of exposure to drugs of abuse during development.